Cardiovascular and respiratory effects of endothelin in the ventrolateral medulla of the normotensive rat.

We studied the relevance of the ventrolateral medulla for the cardiovascular and respiratory effects of endothelin-1 in urethane-anesthetized rats. Microinjection of endothelin-1 into the rostral ventrolateral medulla (RVLM) evoked pressor and bradycardic effects followed by sustained decreases in blood pressure, bradycardia, and respiratory depression. These effects were inhibited by endothelin-A receptor antagonists (BQ-123 and BQ-610) but not by endothelin-B antagonists. In the caudal ventrolateral medulla (CVLM) endothelin-1 decreased blood pressure, renal sympathetic nerve activity, respiratory frequency, and phrenic nerve activity, whereas heart rate increased. Pretreatment with BQ-123 in the CVLM increased respiratory frequency by 15 +/- 6 breaths per minute and prevented the effects of intra-CVLM administration of endothelin-1. In separate experiments, the intracisternal administration of endothelin-1 (20 pmol) to rats pretreated with saline in both RVLM and CVLM resulted in a hypotensive and bradycardic phase that was followed by hypertension (50 +/- 15 mm Hg), bradycardia, and 100% mortality. In a separate group, pretreatment with BQ-123 in the RVLM and CVLM completely inhibited the hypotensive phase and reduced by 83% the subsequent rise in blood pressure evoked by endothelin-1. Cardiorespiratory arrest was prevented in all the rats in this group. Selective endothelin receptor blockade in the RVLM attenuated the hypertensive period of intracisternal administration of endothelin-1 and prevented mortality by 33%, whereas in the CVLM the endothelin receptor antagonist inhibited the initial hypotension and reduced mortality by 25%. Our results support the concept that in the ventral medulla, endothelin-1 can modulate cardiovascular and respiratory function.